Particulate product comprising pantethine

ABSTRACT

A particulate containing a pantethine, a light anhydrous silicic acid and a microcrystalline cellulose, in which the total content of the light anhydrous silicic acid the microcrystalline cellulose amounts to a quantity that yields a 0.6 or higher adsorptivity. The present pantethine-containing particulate has a good flowability and an adequate particle size providing excellent handling properties. It is free from impediments such as blocking, and has a good storage stability.

FIELD OF THE INVENTION

The present invention relates to a pantethine-containing particulate.

BACKGROUND OF THE INVENTION

Pantethine is a useful medicament for: (a) prevention and treatment of apantothenic acid deficiency; (b) replenishment of pantothenic acid topatients suffering from wasting diseases or hyperthyroidism, or topregnant and parturient women or breast-feeding women who have anincreased demand for pantothenic acid that cannot be suppliedsufficiently from foods; and (c) prevention and treatment ofhyperlipidemia, atonic constipation, and side effects of streptomycinand kanamycin, improvement of acute and chronic eczema, and improvementin platelet counts and hemorrhagic tendency in blood dyscrasia, whenthese diseases, disorders or symptoms are presumed to be attributable toa deficiency or a metabolic disorder of pantothenic acid.

Although pantethine exists as an amorphous powder at room temperature,it is supplied as a viscous liquid in the market because it cannotmaintain the powdery state due to its high hygroscopicity, and ThePharmacopoeia of Japan prescribes the pantethine as 80% aqueouspantethine solution. When manufacturing a medicament in the form of asolid dosage form, it is generally desirable to supply the medicament ina powdery state and various studies have so far been done to develop atechnique to powder or solidify pantethine. For example, methods knownfor turning liquid pantethine into powder include a method disclosed inJP-A-S50-88215 comprising freeze-drying pantethine in the presence of asmall quantity of an amino acid or a saccharide having a high eutecticpoint such as glycine, α-alanine, lactose, mannite, or dextran, oranother method disclosed in JP-A-S55-38344 comprising freezing anaqueous pantethine solution, and crushing the resultant congelation,followed by drying.

Further, in order to provide pantethine as soliddosage forms, a numberof attempts have been made including encapsulation of pantethine, ormixing pantethine with a large quantity of starches or similaringredients to obtain a pantethine-containing powder mixture.

SUMMARY OF THE INVENTION

Accordingly, an object of the present invention is to provide apantethine-containing particulate which can be manufactured without suchcumbersome and complicated processes as freezing (freeze-drying)described above. Moreover, it has a high flowability and is free fromimpediments such as blocking. Further, it has an adequate particle sizethat provides excellent handling properties. Yet further, it has a goodstorage stability.

Specifically, the present invention provides a particulate comprisingpantethine, a light anhydrous silicic acid and a microcrystallinecellulose, wherein the total content of the light anhydrous silicic acidand the microcrystalline cellulose amounts to a quantity that has anadsorptivity of 0.6 or higher.

Also, the present invention provides a particulate comprisingpantethine, a light anhydrous silicic acid and a microcrystallinecellulose, wherein the total content of the light anhydrous silicic acidand the microcrystalline cellulose ranges from about 0.7 to about 0.9weight parts per 1 weight part of pantethine.

Further, the present invention provides a particulate substantiallycomprising pantethine, a light anhydrous silicic acid and amicrocrystalline cellulose.

Still further, the present invention provides a solid dosage formcomprising the particulate described above.

According to the present invention, a pantethine-containing particulatecan be provided efficiently.

Further, according to the present invention, a pantethine-containingparticulate which has a good flowability; has an adequate particle sizethat provides excellent handling properties; is free from impedimentssuch as blocking; has a good storage stability can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

Whereas pantethine is available typically in the form of liquid, thepantethine-containing particulate according to the present invention maybe prepared by first adding a solution containing an adequateconcentration of pantethine to a light anhydrous silicic acid and amicrocrystalline cellulose, then agitating the resultant mixture so asto cause the light anhydrous silicic acid and the microcrystallinecellulose to adsorb the pantethine, and then drying the mixture.

More specifically, the pantethine-containing particulate may be preparedby spraying or dripping a pantethine solution of an adequateconcentration (for example, about 60-80 w/w %) onto the light anhydroussilicic acid and the microcrystalline cellulose, as it is or aftersuitably diluting it with water, an alcohol or a hydrous alcohol, in agranulator such as a fluidized-bed granulator, a rotary fluidized-bedgranulator, or an agitating granulator, and then drying the thus treatedmixture. The pantethine-containing granulated substance or particulateof the present invention may also be prepared by first dispersing a partof the light anhydrous silicic acid and/or microcrystalline cellulose ina pantethine solution of an adequate concentration or in its suitablydiluted solution with water, an alcohol or an hydrous alcohol, thenspraying or adding the resultant dispersion onto or to the remainder ofthe light anhydrous silicic acid and/or the microcrystalline cellulosein the granulator, and finally drying the same. The latter methodprovides more efficient preparation of the pantethine-containingparticulate in that the light anhydrous silicic acid and/ormicrocrystalline cellulose may be added in a quantity larger than themaximum amount that can be loaded in the granulator. Since pantethinehas high hygroscopicity, it is preferred to reduce the moisture contentof the granulated substance thus prepared, preferably to 2.0% or below,more preferably to 1.5% or below and most preferably to 1.0% or below.

The particulate obtained may be screened through a sieve with a desiredmesh size for classification into a particulate having a desiredparticle size (powders, fine granules, granules, etc.) According to thepresent invention, a particulate with an average particle size of 120 to280 μm providing excellent handling properties can be readily obtained.

Further, according to the present invention, the light anhydrous silicicacid and the microcrystalline cellulose are contained in the particulateso that the total content of the light anhydrous silicic acid and themicrocrystalline cellulose yields an adsorptivity of about 0.6 or aboveand more preferably from about 0.6 to about 0.7 per 1 weight part ofpantethine. The adsorptivity as herein used refers to a value obtainedby the following manner; define the adsorptivity of 1 as the weightcontent 66 mg of the light anhydrous silicic acid (Aerosil 200; producedby Nippon Aerosil Co., Ltd., Tokyo, Japan) which is required to adsorb100 mg of pantethine as determined in the applicable test 1 describedlater; and divide said required weight content of light anhydroussilicic acid (66 mg) by the weight content of a substance required toadsorb 100 mg of pantethine. For example, a 181 mg weight content ofmicrocrystalline cellulose (Avicel PH-101; produced by Asahi KaseiCorporation, Osaka, Japan) is required as shown in the below-describedapplicable test 1 and thus its adsorptivity is determined as 0.36 =(66(mg)/181 (mg)). The adsorptivity based on the total content of the lightanhydrous silicic acid (Aerosil 200) and the microcrystalline cellulose(Avicel PH-101) is determined as (light anhydrous silicic acid weightcontent)/(pantethine weight content)×1+(microcrystalline celluloseweight content)/(pantethine weight content)×0.36. Thus, it is determinedas 139.64/200×1+24/200×0.36=0.74 based on the Formulation 1 to bedescribed herein later.

The Formulation 6 shown in examples to be described later represents aparticulate prepared using two ingredients, namely pantethine and lightanhydrous silicic acid, and the light anhydrous silicic acid contentthereof had an adsorptivity of 0.67 per 1 weight part of pantethine. Theadsorptivity falls within the preferable range of adsorptivity specifiedby the present invention; however, the particulate of this formulationis undesirable due to its poor storage stability (cf. applicable test 3to be described later). Meanwhile, formulations comprising threeingredients, namely pantethine, a light anhydrous silicic acid and amicrocrystalline cellulose, result in desirable particulates having apreferred adsorptivity as well as an excellent storage stability.

Also, according to the present invention, the total content of the lightanhydrous silicic acid and the microcrystalline cellulose rangespreferably from 0.7 to 0.9 weight parts and more preferably from 0.75 to0.85 weight parts per 1 weight part of pantethine. In this connection,it is preferred that the adsorptivity is at least 0.6 and morepreferably ranging from 0.6 to 0.7. Further, the weight ratio of lightanhydrous silicic acid to microcrystalline cellulose in the totalcontent of these two substances ranges preferably from 1 to 6 and morepreferably from 2 to 4 per 1 weight part of pantethine.

Microcrystalline celluloses usable for the present invention includecommercially available products such as Avicel PH-101, PH-102, PH-301,PH-302 and other Avicel series products, and Ceolus KG-801 and otherCeolus series products (both of these series are produced by Asahi KaseiCorporation, Osaka, Japan). Also, such commercially available productsas Aerosil 200 and other Aerosil series products (produced by NipponAerosil Co., Ltd., Tokyo, Japan), and Carplex BS-304, BS-306, BS-304N,CS-500, FPS-500 and other Carplex series products (produced by Shionogi& Co. Ltd., Osaka, Japan) may be used as the light anhydrous silicicacid for the present invention.

In terms of the administration of the present particulate, the higherthe pantethine content of the particulate is, the less the dosage of thepantethine-containing solid medicine can be. This is more advantageousfor securing compliance requirements. Preferably, the particulate of thepresent invention contains at least 50 w/w %, and particularlypreferably from 50 to 60 w/w % of pantethine.

Alternatively, according to the present invention, silicon compoundssuch as calcium silicate, hydrous silicon dioxide, hydrous amorphoussilicon oxide, magnesium silicate, magnesium aluminum silicate,synthetic aluminum silicate, synthetic magnesium sodium silicate,natural aluminum silicate, heavy anhydrous silicic acid, or silicondioxide may be used as the ingredient having an excellent pantethineadsorptivity instead of the light anhydrous silicic acid. These siliconcompounds may be used to substitute for the whole or a part of the lightanhydrous silicic acid. Likewise, a powdered cellulose may be used inplace of the whole of a part of the microcrystalline cellulose. However,it is preferred that the particulate of the present inventionsubstantially comprises pantethine, a light anhydrous silicic acid and amicrocrystalline cellulose.

The particulate provided according to the present invention is usefulfor solid dosage forms and may be used as it is as dosage forms(powders, fine granules, or granules) or may be formulated as desired byusing suitable formulation additives (flavoring agents, coating agents,etc.). The present particulate may be used to prepare tablets, capsulesor the same kind of solid dosage forms based on any known formulationtechniques.

Hereinafter, the present invention will be described in detail based onexamples along with descriptions of applicable tests.

EXAMPLES

Applicable Test 1 Quantitative Measurement of Adsorbed Pantethine

Five gram of each ingredient shown in Table 1 was knead together with apantethine solution (58%), respectively, in a mortar, and a part of thekneaded mixture was taken and subjected to shaping with a die and punchof 15 mmφ in a diameter for single-punch tableting machine for about 1minute by compressing at a rate of 10 mm/min under a pressure (about 50kg) just enough to homogenize the powder layer. After shaping, the upperpunch was replaced with a punch of 6 mmφ in a diameter for single-punchtableting machine, which was placed on the center of the shaped body,and was compressed at a rate of 10 mm/min to pressurize the compacts.The stress exerted when the punch penetrated into the shaped body wasrecorded on a universal testing machine (Strograph C; by Toyo SeikiSeisaku-sho, Ltd., Tokyo, Japan). A slope ΔS of the initially risinglinear portion of each stress-strain curve thus obtained was defined asthe penetration strength, which was used as a measure of the plasticdeformability of each pantethine-containing powder. The point where thepenetration strengths underwent an abrupt change when varied quantitiesof the pantethine solution were added was determined as a plastic limit.Table 1 shows the thus obtained weight of each ingredient required toadsorb 100 mg of pantethine based on the plastic limit specified above.

TABLE 1 Quantity required to adsorb Ingredients Trade names 100 mgpantethine (mg) Light anhydrous Aerosil 200 66 silicic acidMicrocrystalline Avicel PH-101 181 cellulose Microcrystalline AvicelPH-102 172 cellulose

Example 1 Preparation of Pantethine-containing Particulates

First, a binding liquid was prepared by mixing 3.333 kg of an aqueoussolution containing 60 w/w % pantethine (2 kg as pantethine); 800 ml ofpurified water and 320 ml of a 99% dehydrated ethanol, and purifiedwater was added to the mixture to make up a total volume of 4 l.Ingredients (light anhydrous silicic acid and microcrystallinecellulose) were charged in a fluidized bed granulator in an amount shownin Table 2, and mixed for 3 minutes at an inlet-air temperature of about80° C., and then the binding liquid was sprayed onto the thus treatedmixture to granulate it. After completing the spray, the resultantparticulate was dried until its moisture content decreased to 1.0% orbelow (Loss on drying as measured by a Mettler moisture meter at 80° C.,1 d/30 s, 5 g).

TABLE 2 Formulations (mg) Formula- Formula- Formula- Formula- Formula-Formula- Ingredients tion 1 tion 2 tion 3 tion 4 tion 5 tion 6 Aqueouspantethine 333 333 333 333 333 333 solution (200) (200) (200) (200)(200) (200) (as pantethine) Light anhydrous silicic 139.64 120 110 110120 133 acid Microcrystalline 24 43.6 53.6 23 80 — cellulose (Lightanhydrous silicic 0.8182 0.818 0.818 0.665 1.0 0.665 acid +microcrystalline cellulose) vs. pantethine Light anhydrous silicic 5.8182.75 2.05 4.78 1.5 — acid vs. cellulose Total 363.64 363.64 363.64 333400 333 Pantethine content (%) 55 55 55 60 50 60 Adsorptivity 0.74 0.680.65 0.59 0.74 0.67Applicable Test 2 Evaluation of Physical Properties

Each particulate prepared in the above-described Example 1 was subjectedto the following tests. The results of the test are shown in Table 3.

(1) Measurement of Mean Particle Size

For each particulate prepared, a particle size distribution was obtainedby using sieves having different mesh sizes and thence its averageparticle size (μm) was determined based on a relevant log-normaldistribution.

(2) Measurement of Angles of Repose and Rupture

For each particulate prepared, the angle of repose (°) and angle ofrupture (°) were measured by using a powder tester. The angle of ruptureis an angle newly formed by a powder layer when a impact is applied toan accumulative layer of powder forming an angle of repose. The greaterthe difference (differential angle) between the angle of repose and theangle of rupture, the better flowability the powder will have.

TABLE 3 For- For- For- For- For- For- mula- mula- mula- mula- mula-mula- tion 1 tion 2 tion 3 tion 4 tion 5 tion 6 Mean particle 111 144151 292 130 120 size (μm) Angle of 35 35 36 37 36 33 repose (°) Angle of13 15 15 19 19 12 rupture (°) Differential 22 20 21 18 17 21 angle (°)Adsorptivity 0.74 0.68 0.65 0.59 0.74 0.67

As clearly seen from Table 3 above, the particulates prepared in theExample 1 all had a good flowability. Above all, the particulates of theformulations 1, 2 and 3 exhibited an excellent flowability.

Applicable Test 3 Evaluation of Stability

To evaluate the pantethine-containing particulates prepared above fortheir stability, the pantethine content and the quantity of degradationproducts were measured by liquid chromatography in the particulates(formulations 1, 2 and 6) prepared in Example 1 above just after theirpreparation and after 1 month of their storage therefrom at 50° C. aspacked in aluminum foil. The results of the test are shown in Table 4.

Operating Conditions

-   Detector used: An ultraviolet absorption photometer-   Column: A stainless steel column about 4 mm in inside diameter and    about 15 cm in length packed with octadecylsilanized silica gel for    liquid chromatography (5 μm in particle diameter).-   Column temperature: A constant temperature of about 40° C.-   Mobile phase: pH3.5 phosphate buffer/acetonitrile mixed solution    (6:1)-   Flow rate: Adjusted the flow rate so that the retention time of    pantethine is about 13 minutes

TABLE 4 Formulation 1 Formulation 2 Formulation 6 DegradationDegradation Degradation Content products Content products Contentproducts (%) (%) (%) (%) (%) (%) Initial content 96.9 100 97.7 100 98.0100 After 1 month storage in Al 93.9 256 97.0 173 94.2 265 pack at 50°C. Adsorptivity 0.74 0.68 0.67

As is clear from Table 4, the granulated matter of the formulation 2containing all three ingredients of pantethine, light anhydrous silicicacid and microcrystalline cellulose and having adsorptivity of 0.68showed the most excellent stability in that the highest pantethinecontent remained therein after 1 month of storage at 50° C. from itspreparation.

Applicable Test 4 Vibration Test

The particulate of the formulation 2 prepared in the Example 1 above wasput in a fiber drum which was secured to a test stage was subjected tovibration test, in which first a vertical vibration of 2.0 G(gravitational acceleration) was applied for 200 minutes, then followedby 0.8 G horizontal vibration for 200 minutes and further 0.75 Gvertical vibration for 100 minutes. After the vibration test, noblocking was observed in the particulate specimen.

Example 2 Preparation of Pantethine-containing Particulates

The particulate prepared in Example 1 was mixed with about 1 wt % ofmagnesium stearate per resulting tablet (pantethine content 200mg/tablet) and the resultant mixture was compressed into tablets using apunch of 9.5 mmφ and 7.5 mmR.

1. A particulate consisting of: pantethine, a light anhydrous silicicacid and a microcrystalline cellulose, wherein a total content of thelight anhydrous silicic acid and the microcrystalline cellulose rangesfrom 0.75 to 0.85 weight parts per 1 weight part of pantethine, and aweight ratio of light anhydrous silicic acid to microcrystallinecellulose in the total content of these two substances is in a rangefrom about 2/1 to about 4/1.
 2. The particulate according to claim 1,wherein a pantethine content is at least 50 w/w %.
 3. The particulateaccording to claim 2, wherein the pantethine content ranges from 50 to60 w/w %.
 4. The particulate according to claim 1, wherein an averageparticle size ranges from 120 to 280 μm.
 5. A solid dosage formcomprising the particulate according to claim
 1. 6. The solid dosageform according to claim 5, wherein the dosage form is selected from thegroup consisting of powders, fine granules, granules, tablets andcapsules.